An indole histone deacetylase family inhibitor with antitumor effects

Abstract

The present invention belongs to the field of medicinal chemistry, and particularly relates to indole derivatives represented by general formula I, and their optically active forms or racemates, diastereoisomer mixtures, and the use of such compounds as SIRT2 inhibitors and their application in anti-pancreatic cancer metastasis. The present invention also relates to pharmaceutical compositions containing such compounds and their pharmaceutically acceptable salts as active ingredients. The present invention also relates to pharmaceutical dosage forms of such compounds containing at least one such compound or its salt, and the dosage forms are selected from one or more of the following: tablets, capsules, injections, suppositories, patches, inhalable powder preparations, suspensions, emulsions or ointments.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicinal chemistry, and particularly relates to an indole histone deacetylase family inhibitor with anti-tumor effects, its preparation method and uses. In particular, the indole histone deacetylase family inhibitor has anti-metastatic activity against pancreatic cancer. Background Art

[0002] Silent information regulator (SIRT) is a class of deacetylases highly conserved from bacteria to humans. It has high homology in sequence and cellular function, and its catalytic activity depends on nicotinamide adenine dinucleotide (NAD + ), removing the acetyl group from acetylated proteins to produce nicotinamide (NAM) and acetyl ester metabolites. SIRT is modified in cells after translation and plays very important roles, such as DNA recognition, protein-protein interaction, and maintaining protein stability. SIRT belongs to the class III histone deacetylase family. In mammals, SIRT is one of the key proteins involved in various tumorigenesis and metastasis processes and is related to multiple cancer-related events.

[0003] SIRT2 plays an important regulatory role in the processes of cell invasion and metastasis, involving tumor metastasis processes such as epithelial-mesenchymal transition (EMT), lymph node metastasis, and angiogenesis. Research shows that SIRT2 can promote the metastasis of various tumors such as colorectal cancer, gastric cancer, non-small cell lung cancer, and renal cancer, while knocking out SIRT2 inhibits the metastasis of colorectal cancer, gastric cancer, liver cancer, renal cancer, and breast cancer. Therefore, in combination with the role of SIRT2 in cell regulation, developing new SIRT2 inhibitors is of great significance for treating the occurrence, invasion, and metastasis of malignant tumors.

[0004] Although significant progress has been made in the early detection and treatment of many malignant tumors, pancreatic cancer is usually diagnosed at an advanced stage, and the conventional treatment effect is very poor, with a 5-year survival rate as low as only 2-9%. Surgical resection is the only possible curative treatment method for pancreatic cancer patients. However, among these patients, only 20% of the patients can have the tumor resected surgically at the time of diagnosis, and the remaining 80% of the patients are diagnosed with locally advanced or metastatic diseases and do not meet the surgical conditions. Therefore, chemotherapy remains the first-line treatment method for advanced metastatic pancreatic cancer. Thus, finding more effective targeted drugs to inhibit the metastasis of pancreatic cancer has always been a research hotspot.

[0005] Studies have shown that in pancreatic cancer cells, the expression of SIRT2 is elevated, which inhibits the acetylation of LDH-A at K5, increases its activity and protein level, thereby accelerating glycolysis and lactate production. Lactate has been shown to regulate the microenvironment and promote the interaction between cancer cells and stromal cells, ultimately leading to cancer cell migration. In addition, the LDH-A gene is a direct target of the Myc protein, and the expression of the Myc protein is upregulated in pancreatic cancer cells, resulting in increased LDH-A expression. SIRT2 can stabilize the expression of the C-Myc protein and promote the growth of tumor cells with Myc overexpression. Therefore, SIRT2 inhibitors play a very important role in the proliferation and metastasis of pancreatic cancer cells.

[0006] There have been many related literature reports on indole compounds, and such compounds have a variety of biological activities. Based on a large number of literature investigations, the present invention designed and synthesized a series of novel indole derivatives substituted at the 1, 3, and 5 positions, and conducted anti-tumor activity tests. Surprisingly, it was found that the indole derivatives exhibited anti-metastatic activity against pancreatic cancer. Summary of the Invention

[0007] The object of the present invention is to derivatively design and synthesize a class of novel substituted indole derivatives based on the original work and conduct anti-tumor activity tests. The present invention surprisingly found that the indole derivatives exhibited anti-metastatic activity against pancreatic cancer.

[0008] To achieve the object of the present invention, the following technical solutions can be adopted:

[0009] In the first aspect, the present invention provides a novel indole derivative having the following general formula (I) or a pharmaceutically acceptable salt thereof or an optically active form thereof:

[0010]

[0011] Wherein:

[0012] R 1 、R 2 、R 3 are each simultaneously any one of the following groups: (1) H atom, (2) hydroxyl group, (3) halogen atom, (4) cyano group, (5) nitro group, (6) trihalomethyl group, (7) C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkylsulfonylamino, C 1-18 alkoxycarbonyl, C 1-18 alkoxysulfonyl, C 1-6 alkoxy, C 2-6 alkenyloxy, C2-6 alkynyloxy, C 1-6 alkylthio, C 2-6 alkenylthio, C 2-6 alkynylthio, C 1-6 alkylsulfonyl, C 2-6 alkenylsulfonyl, C 2-6 alkynylsulfonyl, C 1-6 alkylsulfinyl, C 2-6 alkenylsulfinyl, C 2-6 alkynylsulfinyl, C 3-8 cycloalkenyl, each of the above groups being optionally substituted by one or more substituents selected from H atom, halogen atom, hydroxyl group, cyano group, nitro group or amino group, (8) variously substituted carbonyl groups, which are optionally substituted by one or more substituents selected from H atom, hydroxyl group, C 1-6 alkyl group, amino group, C 1-6 alkylamino group, C 1-6 alkoxy group, C 1-6 alkylthio group and C 3-8 cycloalkyl group, (9) variously substituted amino groups, which are optionally substituted by one or more substituents selected from H atom, C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 1-6 alkylsulfonyl group, C 2-6 alkenylsulfonyl group, C 2-6 alkynylsulfonyl group, C 1-6 alkylcarbonyl group, C 2-6 alkenylcarbonyl group or C 2-6 alkynylcarbonyl group, (10) variously substituted phenyl groups, variously substituted benzyl groups, variously substituted benzyloxy groups, variously substituted benzoyl groups, variously substituted benzenesulfonyl groups, variously substituted pyridine rings, variously substituted pyrazole rings, variously substituted pyrrole rings, variously substituted pyrimidine rings, variously substituted quinoline rings, variously substituted isoquinoline rings, variously substituted imidazole rings, variously substituted morpholine rings, variously substituted piperazine rings, variously substituted pyridazine rings, variously substituted pyrazine rings, variously substituted piperidine rings, variously substituted thiophene rings, variously substituted thiazole rings, variously substituted isothiazole rings, variously substituted benzothiazole rings, variously substituted pyran rings, variously substituted indole rings, variously substituted oxazole rings, variously substituted isoxazole rings, variously substituted triazole rings, variously substituted benzotriazole rings, variously substituted furan rings, each of the above groups being optionally substituted by one or more substituents selected from H, halogen, C 1-6 alkyl group, C 1-6 alkylamino group, C 3-7 cycloalkyl group, C 1-6 alkoxy group, C 1-6Alkanesulfonamido, benzyloxycarbonyl, C 1-18 Alkoxycarbonyl, C 1-18 Alkoxysulfonyl, trifluoromethyl, hydroxy, cyano, nitro and amino, and is substituted by one or more substituents selected therefrom, (11) adjacent R 1 and R 2 are connected to form an alkanediyloxy group.

[0013] As an alternative, in the above compound or a pharmaceutically acceptable salt thereof or an optically active form thereof, wherein R 1 , R 2 are each independently any one of the following groups: (1) H atom, (2) hydroxy, (3) halogen atom, (4) nitro, (5) C 1-4 alkyl, C 1-4 alkoxy, any of the above groups being optionally substituted by one or more substituents selected from hydrogen atom, halogen atom, hydroxy, cyano, nitro and amino, (6) phenyl substituted with various substituents, benzyloxy substituted with various substituents, any of the above groups being optionally substituted by H, halogen, C 1-6 alkyl, C 1-6 alkylamino, C 3-7 cycloalkyl, C 1-4 alkoxy, C 1-4 alkanesulfonamido, benzyloxycarbonyl, C 1-10 alkoxycarbonyl, C 1-10 alkoxysulfonyl, trifluoromethyl, hydroxymethyl, hydroxy, cyano, nitro and amino, and is substituted by one or more substituents selected therefrom.

[0014] As an alternative, in the above compound or a pharmaceutically acceptable salt thereof or an optically active form thereof, wherein R 1 , R 2 , R 3 are each independently any one of the following groups: (1) H atom, (2) hydroxy, (3) fluorine, chlorine, bromine, (4) nitro, (5) C 1-4 alkyl, C 1-4 alkoxy, any of the above groups being optionally substituted by one or more substituents selected from hydrogen atom, halogen atom, hydroxy, cyano, nitro and amino, (6) phenyl, benzyloxy, unsubstituted or substituted, the substituents being selected from H, halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, one or more of which.

[0015] As an alternative, in the above compound or a pharmaceutically acceptable salt thereof or an optically active form thereof, wherein R 1 , R 2 , R 3Each is simultaneously any one of the following groups: ethoxycarbonyl, H atom, hydroxyl group, bromine atom, chlorine atom, methoxy group, ethoxy group, 2-methyl-phenyl, 4-methyl-phenyl, benzyloxy group or adjacent R 1 and R 2 are connected to form an alkanediyloxy group.

[0016] As an alternative, in the above compound or its pharmaceutically acceptable salt or its optically active form, the compound is selected from:

[0017]

[0018]

[0019]

[0020]

[0021] In a second aspect, the synthetic route for preparing the indole derivatives of the general formula (I) of the present invention or pharmaceutically acceptable salts or their optically active forms or racemates, diastereoisomeric mixtures is as follows: where R 1 , R 2 , R 3 is the same as described in the first aspect above.

[0022] Using 5-bromoindole-3-acetic acid to carry out a substitution reaction in the presence of NaH to obtain intermediate A-1, intermediate A-1 is subjected to acid-amine condensation to obtain intermediate A-2, and intermediate A-2 is in Pd(PPh 3 ) 4 , Na 2 CO 3 ethanol and water system, and carry out a suzuki coupling reaction to synthesize compounds Z1-1 to Z1-6 and Z2-1 to Z2-7 in the general formula I, where R 1 , R 3 is the same as described in claim 1.

[0023]

[0024] Reagents and conditions: a. NaH, DMF, 0 °C to r.t., b. HATU, DIEA, DMF, r.t. / EDCI, HOBT, TEA, DMF, r.t., c. Pd(PPh 3 ) 4 , Na 2 CO 3 , EtOH, water, 100 °C, reflux / Pd(PPh 3 ) 4 , K 2 CO3 , toluene, water, 110 °C, reflux.

[0025] Using 5-bromoindole-3-acetic acid to carry out an esterification reaction to obtain intermediate B-1, and then obtaining intermediate B-2 through a Suzuki coupling reaction. Intermediate B-2 undergoes a hydrolysis reaction to obtain intermediate B-3, and then a substitution reaction occurs under the action of NaH to obtain intermediate B-4. Finally, an acid amide condensation reaction is carried out to synthesize compounds Z3-1 to Z3-12 in general formula I.

[0026]

[0027] Reagents and conditions: a. MeOH, SOCl 2 , 0 °C to r.t., b. Pd(PPh 3 ) 4 , K 2 CO 3 , toluene, water, 110 °C, reflux. c. NaOH, CH 3 OH, HCl. d. NaH, DMF, ice water, r.t., e. HATU, DIEA, DMF, r.t. / EDCI, HOBt, TEA, DMF, r.t..

[0028] In a third aspect, the present invention provides a pharmaceutical composition, which comprises the compound described in the first aspect above, or a pharmaceutically acceptable salt thereof, or an optically active form thereof, and a pharmaceutically acceptable carrier.

[0029] In a fourth aspect, the present invention provides a pharmaceutical preparation, which comprises the pharmaceutical composition described in the third aspect above, and the dosage form of the pharmaceutical preparation is selected from one or more of the following: tablets, capsules, injections, suppositories, patches, inhalable powder preparations, suspensions, emulsions or ointments.

[0030] In a fifth aspect, the present invention provides the use of the compound described in the first aspect above, or a pharmaceutically acceptable salt thereof, or an optically active form thereof, or the pharmaceutical composition described in the third aspect, or the pharmaceutical preparation described in the fourth aspect in the preparation of an SIRT2 inhibitor.

[0031] In a sixth aspect, the present invention provides the use of the compound described in the first aspect above, or a pharmaceutically acceptable salt thereof, or an optically active form thereof, or the pharmaceutical composition described in the third aspect, or the pharmaceutical preparation described in the fourth aspect in the preparation of an anti-tumor drug.

[0032] As an alternative, in the above applications, the anti-tumor drug has anti-pancreatic cancer metastasis activity.

[0033] The present invention has the following beneficial effects compared with the prior art:

[0034] The present invention derivatively designs and synthesizes a new type of substituted indole derivatives and conducts anti-tumor activity tests. It is unexpectedly found that the indole derivatives exhibit anti-metastatic activity against pancreatic cancer. The present invention provides a new idea for exploring drugs that can effectively treat pancreatic cancer and has important clinical significance. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 : Quantitative results of the cell viability of compounds Z1-1 to Z1-6.

[0036] Figure 2 : Quantitative results of the cell viability of compounds Z2-1 to Z2-7.

[0037] Figure 3 : Results of the scratch assay of compounds Z1-1 to Z1-6. Among them, Figure 3 A is a photograph of cell migration at 48 h, Figure 3 B is the result of the migration rate assay of compounds Z1-1 to Z1-6.

[0038] Figure 4 : Results of the scratch assay of compounds Z2-2 to Z2-4, Z1-4 and Z2-7. DETAILED DESCRIPTION OF THE INVENTION

[0039] The present invention will be further described below with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the scope of the present invention.

[0040] For those technical or conditions not specified in the examples, they shall be in accordance with the techniques or conditions described in the literature in this field or in accordance with the product specifications. For the reagents or instruments whose manufacturers are not indicated, they are all conventional products that can be obtained through regular channels.

[0041] The experimental methods in the following examples are all conventional methods unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.

[0042] Example 1: 2-(1-Isopropyl-5-(quinolin-8-yl)-1H-indol-3-yl)-N-(4-methoxybenzyl)acetamide (Z1-1)

[0043] Dissolve 5-bromoindole-3-acetic acid (1a, 10.00 g, 39.36 mmol) in 100 mL of anhydrous DMF. Then, slowly add NaH (60% content, 7.97 g, 118.08 mmol) portionwise to the solution under an ice bath. After addition, remove the ice bath and stir the reaction at room temperature for 0.5 h. Then, slowly add 2-bromopropane (2a, 5.32 g, 43.3 mmol) dropwise to the reaction mixture and continue to stir at room temperature for 1 h, and monitor the reaction by TLC. After the reaction is detected to be complete, concentrate the reaction solution to about 50 mL, add 500 mL of water, and adjust the pH to 4 - 5 with 1 M hydrochloric acid. A large amount of solid precipitates. Extract with ethyl acetate (100 mL × 3), combine the organic layers, wash with saturated brine (50 mL × 2), and then concentrate. Column chromatography (DCM:MeOH = 20:1) gives 9.70 g of a yellow oily liquid. Dissolve it in 100 mL of anhydrous DMF, slowly add HATU (7.48 g, 19.66 mmol) and DIEA (12.75 g, 6.38 mmol) under an ice bath. After addition, remove the ice bath and react at room temperature for 0.5 h. After monitoring the reaction of the starting materials to completion by TLC, add 4-methoxybenzylamine (4a, 2.48 g, 18.01 mmol), and react at room temperature for 1 h and then monitor by TLC. After the monitored reaction is complete, concentrate the reaction solution to about 50 mL, add 500 mL of water, and adjust the pH to 4 - 5 with 1 M hydrochloric acid. A large amount of solid precipitates. Extract with ethyl acetate (100 mL × 3), combine the organic layers, wash with saturated brine (50 mL × 2), and then concentrate. Column chromatography (PE:EA = 2:1) gives 5.22 g of a yellow powdery solid. At room temperature, dissolve 8-quinolineboronic acid (1b, 0.50 g, 2.31 mmol) in 18 mL of toluene, add the intermediate obtained in the previous step (0.8 g, 1.93 mmol), then add K 3 PO 4 (1.23 g, 5.78 mmol) and dissolve it by adding 3 mL of water. After stirring for 15 min, add Pd(PPh 3 ) 4 (0.36 g, 0.31 mmol). Under nitrogen protection, reflux the reaction at 110 °C for 6 h. After monitoring the reaction of the starting materials to completion by TLC, filter off the insoluble impurities, concentrate the solvent, add ethyl acetate (50 mL), wash with saturated brine (50 mL × 2), and then concentrate. Column chromatography (PE:EA = 10:1) gives a yellow oily liquid. Add anhydrous ether (20 mL) for slurrying, a large amount of solid precipitates. After suction filtration and drying, 0.19 g of a white powdery solid is obtained, with a yield of 21.3%.

[0044] 11H NMR (600 MHz, DMSO) δ 8.87 (dd, J = 4.0, 1.8 Hz, 1H), 8.42 (dd, J = 8.3, 1.8 Hz, 1H), 8.37 (t, J = 5.9 Hz, 1H), 7.97 (dd, J = 8.1, 1.4 Hz, 1H), 7.79 (d, J = 1.3 Hz, 1H), 7.72 (dd, J = 7.1, 1.5 Hz, 1H), 7.69–7.65 (m, 1H), 7.55 (dd, J = 8.3, 4.1 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.5, 1.6 Hz, 1H), 7.36 (s, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.70–6.63 (m, 2H), 4.80–4.73 (m, 1H), 4.17 (d, J = 5.9 Hz, 2H), 3.63 (s, 3H), 3.58 (s, 2H), 1.50 (s, 3H), 1.48 (s, 3H). 13 13C NMR (150 MHz, DMSO) δ 170.92 (s), 158.52 (s), 150.40 (s), 146.18 (s), 142.12 (s), 136.81 (s), 135.17 (s), 131.98 (s), 130.48 (d, J = 13.4 Hz), 128.92 (d, J = 7.4 Hz), 127.86 (s), 127.41 (s), 126.81 (s), 125.04 (s), 123.93 (s), 121.68 (s), 121.36 (s), 113.94 (s), 109.53 (s), 109.17 (s), 55.44 (s), 46.97 (s), 42.13 (s), 33.28 (s), 23.06 (s). ESI-HRMS: calcd for C 30 H 29 N 3 O 2 , [M+H] + , 464.2260, found 465.2333.

[0045] Example 2: 2-(5-([1,1'-Biphenyl]-3-yl)-1-isopropyl-1H-indol-3-yl)-N-(4-methoxybenzyl)acetamide (Z1-2)

[0046] The preparation method of the compound of Example 2 is the same as that of Example 1, except that 3-biphenylboronic acid is used instead of 8-quinolineboronic acid in the first step, and a white solid powder is obtained with a yield of 23.6%.

[0047] 11H NMR (600 MHz, DMSO) δ 8.47 (t, J = 5.9 Hz, 1H), 7.95 (d, J = 1.2 Hz, 1H), 7.88 (s, 1H), 7.74 (d, J = 7.3 Hz, 2H), 7.62 (d, J = 7.6 Hz, 1H), 7.59 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.55–7.51 (m, 2H), 7.49 (t, J = 7.7 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.36 (s, 1H), 7.14 (t, J = 9.4 Hz, 2H), 6.70 (d, J = 8.6 Hz, 2H), 4.76 (dq, J = 13.3, 6.6 Hz, 1H), 4.20 (d, J = 5.9 Hz, 2H), 3.62 (s, 3H), 3.62 (s, 2H), 1.47 (s, 3H), 1.46 (s, 3H). 13 13C NMR (150 MHz, DMSO) δ 170.93 (s), 158.54 (s), 142.94 (s), 141.31 (s), 141.00 (s), 135.55 (s), 131.98 (s), 131.45 (s), 129.82 (s), 129.40 (s), 128.92 (s), 128.59 (s), 127.94 (s), 127.39 (s), 126.36 (s), 125.61 (s), 125.19 (s), 124.45 (s), 120.91 (s), 118.06 (s), 113.99 (s), 110.65 (s), 109.84 (s), 46.98 (s), 42.13 (s), 33.24 (s), 23.02 (s). ESI-HRMS: calcd for C 33 H 32 N 2 O 2 , [M+H] + , 489.2464, found 489.2524.

[0048] Example 3: 2-(1-Isopropyl-5-(2-phenoxyphenyl)-1H-indol-3-yl)-N-(4-methoxybenzyl)acetamide (Z1-3)

[0049] The compound of Example 3 was prepared in the same manner as in Example 1, except that 2-phenoxybenzeneboronic acid was used instead of 8-quinolineboronic acid in the first step and petroleum ether was used instead of anhydrous diethyl ether in the last step to obtain a white solid powder with a yield of 22.8%.

[0050] 11H NMR (600 MHz, DMSO) δ 8.37 (t, J = 5.9 Hz, 1H), 7.72 (d, J = 1.3 Hz, 1H), 7.46 (dd, J = 7.6, 1.7 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.35 (td, J = 7.8, 1.7 Hz, 1H), 7.32–7.29 (m, 2H), 7.29–7.28 (m, 1H), 7.28–7.26 (m, 2H), 7.15 (d, J = 8.6 Hz, 2H), 7.00 (t, J = 7.3 Hz, 2H), 6.90–6.86 (m, 2H), 6.80–6.74 (m, 2H), 4.68 (dt, J = 13.3, 6.6 Hz, 1H), 4.18 (d, J = 5.9 Hz, 2H), 3.69 (s, 3H), 3.54 (s, 2H), 1.42 (s, 3H), 1.41 (s, 3H). 13 13C NMR (150 MHz, DMSO) δ 170.83 (s), 158.59 (s), 157.98 (s), 153.18 (s), 135.17 (d, J = 17.8 Hz), 132.01 (d, J = 13.7 Hz), 130.28 (s), 129.01 (s), 128.63 (s), 128.21 (s), 128.03 (s), 124.91 (s), 124.08 (s), 123.04–122.96 (m), 122.86 (d, J = 25.4 Hz), 120.83 (s), 120.08 (s), 117.85 (s), 114.03 (s), 109.71 (s), 109.57 (s), 55.51 (s), 46.88 (s), 42.13 (s), 33.15 (s), 23.03 (s). ESI-HRMS: calcd for C 33 H 32 N 2 O 3 , [M+H] + , 505.2413, found 505.2485.

[0051] Example 4: 2-(1-Isopropyl-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(4-methoxybenzyl)acetamide (Z1-4)

[0052] The compound of Example 4 was prepared in the same manner as in Example 1, except that 6-quinolineboronic acid was used instead of 8-quinolineboronic acid in the first step, to obtain a white solid powder with a yield of 25.4%.

[0053] 11H NMR (600 MHz, DMSO) δ 8.88 (dd, J = 4.1, 1.4 Hz, 1H), 8.47 (t, J = 5.9 Hz, 1H), 8.39 (dd, J = 8.3, 1.1 Hz, 1H), 8.20 (s, 1H), 8.08 (s, 2H), 8.03 (s, 1H), 7.61 (s, 2H), 7.55 (dd, J = 8.2, 4.1 Hz, 1H), 7.39 (s, 1H), 7.16 (d, J = 8.5 Hz, 2H), 6.70 (d, J = 8.5 Hz, 2H), 4.77 (dt, J = 13.3, 6.6 Hz, 1H), 4.22 (d, J = 5.9 Hz, 2H), 3.64 (s, 2H), 3.58 (s, 3H), 1.47 (d, J = 6.6 Hz, 6H). 13 13C NMR (150 MHz, DMSO) δ 170.89 (s), 158.53 (s), 150.45 (s), 147.22 (s), 140.19 (s), 136.46 (s), 135.70 (s), 132.08 (s), 130.50 (s), 129.66 (d, J = 19.1 Hz), 129.00 (s), 128.74 (d, J = 15.1 Hz), 124.94 (s), 124.63 (s), 122.20 (s), 121.00 (s), 118.41 (s), 113.99 (s), 110.87 (s), 109.98 (s), 55.33 (s), 47.06 (s), 42.14 (s), 33.24 (s), 23.03 (s). ESI-HRMS: calcd for C 30 H 29 N 3 O 2 , [M+H] + , 464.2260, found 464.2333.

[0054] Example 5: 2-(1-Isopropyl-5-(isoquinolin-5-yl)-1H-indol-3-yl)-N-(4-methoxybenzyl)acetamide (Z1-5)

[0055] The compound of Example 5 was prepared in the same manner as in Example 1, except that 5-isoquinolineboronic acid was used instead of 8-quinolineboronic acid in the first step, to give a white solid powder with a yield of 26.1%.

[0056] 11H NMR(600MHz,DMSO)δ9.39(s,1H),8.45(d,J=6.0Hz,1H),8.39(t,J=5.8Hz,1H),8.14(d,J=8.1Hz,1H),7.78–7.75(m,2H),7.72–7.70(m,2H),7.64(d,J=8.4Hz,1H),7.43(s,1H),7.26(dd,J=8.4,1.6Hz,1H),7.07(d,J=8.6Hz,2H),6.65(d,J=8.6Hz,2H),4.83–4.78(m,1H),4.16(d,J=5.9Hz,2H),3.63(s,3H),3.59(s,2H),1.50(s,3H),1.49(s,3H). 13 13C NMR(150MHz,DMSO)δ170.84(s),158.52(s),153.25(s),143.56(s),140.43(s),135.39(s),134.15(s),131.92(s),131.55(s),129.25(d,J=16.4Hz),128.92(s),128.26(s),127.61(s),126.96(s),124.67(s),123.37(s),120.90(s),118.87(s),113.93(s),110.31(s),109.70(s),47.06(s),42.12(s),33.21(s),23.08(s).ESI-HRMS:calcd forC 30 H 29 N 3 O 2 ,[M+H] + ,464.2260,found 464.2333.

[0057] Example 6: 2-(1-Isopropyl-5-(phenanthren-9-yl)-1H-indol-3-yl)-N-(4-methoxybenzyl)acetamide (Z1-6)

[0058] The compound of Example 6 was prepared in the same manner as in Example 1, except that 9-phenanthreneboronic acid was used instead of 8-quinolineboronic acid in the first step, to obtain a white solid powder with a yield of 20.1%.

[0059] 11H NMR (600 MHz, DMSO) δ 8.95 (d, J = 8.3 Hz, 1H), 8.89 (d, J = 8.2 Hz, 1H), 8.39 (t, J = 5.7 Hz, 1H), 8.01 (d, J = 7.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 2.5 Hz, 2H), 7.73–7.66 (m, 3H), 7.63 (d, J = 8.4 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.43 (s, 1H), 7.28 (dd, J = 8.3, 1.3 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.58 (d, J = 8.5 Hz, 2H), 4.81 (dt, J = 13.3, 6.6 Hz, 1H), 4.16 (d, J = 5.8 Hz, 2H), 3.59 (s, 2H), 3.52 (s, 3H), 1.52 (s, 3H), 1.51 (s, 3H). 13 13C NMR (150 MHz, DMSO) δ 170.91 (s), 158.47 (s), 140.01 (s), 135.28 (s), 131.91–131.56 (m), 130.86 (s), 130.64 (s), 129.66 (s), 128.92 (d, J = 7.7 Hz), 128.14 (s), 127.64 (s), 127.50 (s), 127.33–126.97 (m), 124.52 (s), 123.67 (d, J = 18.8 Hz), 123.25 (s), 120.72 (s), 113.90 (s), 110.03 (s), 109.57 (s), 55.32 (s), 47.09 (s), 42.15 (s), 33.22 (s), 23.09 (s). ESI-HRMS: calcd for C 35 H 32 N 2 O 2 , [M+H] + , 513.2464, found 513.2537.

[0060] Example 7: N-(4-Cyanobenzyl)-2-(1-isopropyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetamide (Z2-1)

[0061] Dissolve 5-bromoindole-3-acetic acid (1a, 10.00 g, 39.36 mmol) in 100 mL of anhydrous DMF. Then, slowly add NaH (60% content, 7.97 g, 118.08 mmol) portionwise to the solution under an ice bath. After addition, remove the ice bath and stir the reaction at room temperature for 0.5 h. Then, slowly add 2-bromopropane (2a, 5.32 g, 43.3 mmol) dropwise to the reaction solution and continue to stir at room temperature for 1 h, and monitor the reaction by TLC. After the reaction is detected to be complete, concentrate the reaction solution to about 50 mL, add 500 mL of water, and adjust the pH to 4 - 5 with 1 M hydrochloric acid. A large amount of solid precipitates. Extract with ethyl acetate (100 mL × 3), combine the organic layers, wash with saturated brine (50 mL × 2), and then concentrate. Column chromatography (DCM:MeOH = 20:1) gives 9.70 g of a yellow oily liquid. Dissolve it in 100 mL of anhydrous DMF, slowly add HATU (0.75 g, 1.97 mmol) and DIEA (1.28 g, 0.64 mmol) under an ice bath. After addition, remove the ice bath and react at room temperature for 0.5 h. After monitoring by TLC that the raw materials have reacted completely, add 4-cyanobenzylamine (4a, 0.24 g, 1.80 mmol) and react at room temperature for 1 h, and then monitor by TLC. After the monitored reaction is complete, concentrate the reaction solution to about 50 mL, add 500 mL of water, and adjust the pH to 4 - 5 with 1 M hydrochloric acid. A large amount of solid precipitates. Extract with ethyl acetate (100 mL × 3), combine the organic layers, wash with saturated brine (50 mL × 2), and then concentrate. Column chromatography (PE:EA = 2:1) gives 0.60 g of a yellow powdery solid. At room temperature, dissolve 6-quinolineboronic acid (1b, 0.29 g, 1.76 mmol) in 18 mL of toluene, add the intermediate obtained in the previous step (0.60 g, 1.47 mmol), then add K 3 PO 4 (0.93 g, 4.41 mmol) and dissolve it by adding 3 mL of water. After stirring for 15 min, add Pd(PPh 3 ) 4 (0.27 g, 0.24 mmol). Under nitrogen protection, reflux the reaction at 110 °C for 6 h. After monitoring by TLC that the raw materials have reacted completely, filter to remove insoluble impurities, concentrate the solvent, add ethyl acetate (50 mL), wash with saturated brine (50 mL × 2), and then concentrate. Column chromatography (PE:EA = 10:1) gives a yellow oily liquid. Add anhydrous ether (20 mL) for pulping, a large amount of solid precipitates. After suction filtration and drying, 0.16 g of a white powdery solid is obtained, with a yield of 23.8%.

[0062] 11H NMR (600 MHz, DMSO) δ 8.88 (dd, J = 4.1, 1.7 Hz, 1H), 8.63 (t, J = 6.0 Hz, 1H), 8.40 (dd, J = 8.3, 1.5 Hz, 1H), 8.20 (s, 1H), 8.08 (s, 2H), 8.01 (s, 1H), 7.64–7.61 (m, 4H), 7.55 (dd, J = 8.2, 4.2 Hz, 1H), 7.42 (s, 1H), 7.41 (s, 2H), 4.78 (dt, J = 13.3, 6.7 Hz, 1H), 4.36 (d, J = 6.0 Hz, 2H), 3.69 (s, 2H), 1.48 (s, 3H), 1.47 (s, 3H). 13 13C NMR (150 MHz, DMSO) δ 171.38 (s), 150.48 (s), 147.21 (s), 146.14 (s), 140.20 (s), 136.45 (s), 135.70 (s), 132.56 (s), 130.56 (s), 129.74 (s), 129.53 (s), 128.73 (d, J = 17.2 Hz), 128.50 (s), 124.95 (s), 124.63 (s), 122.23 (s), 121.05 (s), 119.20 (s), 118.44 (s), 110.93 (s), 110.10–109.97 (m), 109.71 (s), 47.06 (s), 42.58 (s). ESI-HRMS: calcd for C 30 H 26 N 4 O, [M+H]+, 459.2107, found 459.2179.

[0063] Example 8: 2-(1-Isopropyl-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z2-2)

[0064] The preparation method of the compound of Example 8 is the same as that of Example 7, except that 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide is used instead of 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(4-cyanobenzylamine)acetamide in the first step, and a white solid powder is obtained with a yield of 23.2%.

[0065] 11H NMR (600 MHz, DMSO) δ 8.88 (dd, J = 4.1, 1.7 Hz, 1H), 8.59 (t, J = 5.9 Hz, 1H), 8.41 (ddd, J = 9.5, 6.6, 1.0 Hz, 2H), 8.22 (d, J = 1.8 Hz, 1H), 8.12 (dd, J = 8.8, 2.0 Hz, 1H), 8.10–8.06 (m, 2H), 7.62 (d, J = 0.9 Hz, 2H), 7.58 (td, J = 7.7, 1.8 Hz, 1H), 7.55 (dd, J = 8.3, 4.2 Hz, 1H), 7.44 (s, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.17 (dd, J = 7.0, 5.2 Hz, 1H), 4.78 (dt, J = 13.3, 6.7 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 3.71 (s, 2H), 1.49 (s, 3H), 1.48 (s, 3H). 13 13C NMR (150 MHz, DMSO) δ 171.27 (s), 159.21 (s), 150.46 (s), 149.24 (s), 147.21 (s), 140.16 (s), 136.96 (s), 136.48 (s), 135.69 (s), 130.52 (s), 129.73 (s), 129.57 (s), 128.76 (d, J = 11.1 Hz), 124.95 (s), 124.68 (s), 122.47 (s), 122.22 (s), 121.47 (s), 121.02 (s), 118.41 (s), 110.90 (s), 109.79 (s), 46.82 (s), 44.94 (s), 33.10–32.97 (m), 22.92 (s). ESI-HRMS: calcd for C 28 H 26 N 4 O, [M+Na] + , 457.2107, found 457.2029.

[0066] Example 9: 2-(1-Isopropyl-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-3-ylmethyl)acetamide (Z2-3)

[0067] The compound of Example 9 was prepared in the same manner as in Example 7, except that 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(pyridin-3-ylmethyl)acetamide was used instead of 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(4-cyanobenzylamine)acetamide in the third step, to obtain a white solid powder with a yield of 18.4%.

[0068] 1 1H NMR (600 MHz, DMSO) δ 8.88 (d, J = 2.8 Hz, 1H), 8.59 (t, J = 5.8 Hz, 1H), 8.50 (s, 1H), 8.43–8.40 (m, 1H), 8.39 (d, J = 4.0 Hz, 1H), 8.20 (s, 1H), 8.08 (s, 2H), 8.01 (s, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.62 (s, 2H), 7.55 (dd, J = 8.2, 4.1 Hz, 1H), 7.40 (s, 1H), 7.21 (dd, J = 7.6, 4.8 Hz, 1H), 4.77 (dt, J = 13.3, 6.7 Hz, 1H), 4.32 (d, J = 5.9 Hz, 2H), 3.67 (s, 2H), 1.48 (s, 3H), 1.47 (s, 3H). 13 13C NMR (150 MHz, DMSO) δ 171.29 (s), 150.46 (s), 149.20 (s), 148.46 (s), 140.31–140.17 (m), 136.52 (s), 135.80–135.31 (m), 130.58 (s), 129.66 (d, J = 19.2 Hz), 128.75 (d, J = 17.7 Hz), 124.96 (s), 124.66 (s), 123.81 (s), 122.22 (s), 121.05 (s), 33.34 (s), 23.03 (s). ESI-HRMS: calcd for C 28 H 26 N 4 O, [M+H]+, 435.2107, found 435.2191.

[0069] Example 10: 2-(1-Isopropyl-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(4-methylbenzyl)acetamide (Z2-4)

[0070] The preparation method of the compound of Example 10 was the same as that of Example 7, except that 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(4-methylbenzyl)acetamide was used instead of 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(4-cyanobenzyl)acetamide in the first step, and a pale yellow solid powder was obtained with a yield of 29.6%.

[0071] 11H NMR (600 MHz, DMSO) δ 8.88 (dd, J = 4.1, 1.6 Hz, 1H), 8.50 (t, J = 5.9 Hz, 1H), 8.38 (d, J = 8.3 Hz, 1H), 8.19 (s, 1H), 8.08 (s, 2H), 8.02 (s, 1H), 7.61 (s, 2H), 7.55 (dd, J = 8.2, 4.1 Hz, 1H), 7.40 (s, 1H), 7.11 (d, J = 7.9 Hz, 2H), 6.93 (d, J = 7.7 Hz, 2H), 4.77 (dt, J = 13.3, 6.6 Hz, 1H), 4.24 (d, J = 5.9 Hz, 2H), 3.65 (s, 2H), 2.12 (s, 3H), 1.48 (s, 3H), 1.47 (s, 3H). 13 13C NMR (150 MHz, DMSO) δ 170.95 (s), 140.33 (s), 137.01 (s), 136.46 (s), 136.10 (s), 135.70 (s), 130.54 (s), 129.67 (d, J = 11.9 Hz), 129.15 (s), 128.78 (s), 128.62 (s), 127.68 (s), 124.98 (s), 124.65 (s), 122.13 (s), 121.01 (s), 118.44 (s), 22.85 (s), 21.00 (s). ESI-HRMS: calcd for C 30 H 29 N 3 O, [M+Na] + , 470.2311, found 470.2220.

[0072] Example 11: 2-(1-Isopropyl-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(thiophen-2-ylmethyl)acetamide (Z2-5)

[0073] The preparation method of the compound of Example 11 is the same as that of Example 7, except that 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(thiophen-2-ylmethyl)acetamide is used instead of 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(4-cyanobenzylamine)acetamide in the first step, and a pale yellow solid powder is obtained with a yield of 29.6%.

[0074] 11H NMR (600 MHz, DMSO) δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.63 (t, J = 5.9 Hz, 1H), 8.40 (dd, J = 8.3, 1.6 Hz, 1H), 8.20 (s, 1H), 8.09 (d, J = 1.2 Hz, 2H), 8.01 (d, J = 1.0 Hz, 1H), 7.61 (d, J = 1.1 Hz, 2H), 7.55 (dd, J = 8.2, 4.2 Hz, 1H), 7.39 (s, 1H), 7.30 (dd, J = 5.1, 1.2 Hz, 1H), 6.96–6.94 (m, 1H), 6.88 (dd, J = 5.1, 3.4 Hz, 1H), 4.80–4.74 (m, 1H), 4.46 (d, J = 5.8 Hz, 2H), 3.64 (s, 2H), 1.48 (s, 3H), 1.47 (s, 3H). 13 13C NMR (150 MHz, DMSO) δ 150.44–150.31 (m), 147.21 (s), 143.10–142.97 (m), 140.19 (s), 136.52 (s), 130.54 (s), 129.68 (d, J = 12.5 Hz), 128.74 (d, J = 11.5 Hz), 127.03 (s), 125.77 (s), 125.36–125.23 (m), 124.96 (s), 124.60 (s), 122.21 (s), 120.95 (s), 118.37 (s), 110.86 (s), 109.77 (s), 47.02 (s), 37.54 (s), 32.88 (s), 22.86 (s). ESI-HRMS: calcd for C27H25N3OS, [M+H]+, 440.1718, found 440.1791.

[0075] Example 12: (S)-7-Bromo-10-(N-hydroxyoctanamide)-1,5,10,11a-tetrahydro-3H-benzo[e]pyrrolo[1,2-][1,4]diazepin -3,11(2H)-dione (Z2-6)

[0076] The preparation method of the compound of Example 12 is the same as that of Example 7, except that 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(4-(tert-butyl)benzyl)acetamide is used instead of 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(4-cyanobenzyl)acetamide in the first step, and a white solid powder is obtained with a yield of 28.4%.

[0077] 11H NMR (600 MHz, DMSO) δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.50 (t, J = 5.9 Hz, 1H), 8.40 (dd, J = 8.3, 1.3 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.13 (dd, J = 8.8, 2.1 Hz, 1H), 8.10–8.07 (m, 2H), 7.60 (d, J = 1.4 Hz, 2H), 7.54 (d, J = 4.0 Hz, 1H), 7.40 (s, 1H), 7.14 (d, J = 8.3 Hz, 2H), 7.10–7.07 (m, 2H), 4.80–4.75 (m, 1H), 4.24 (d, J = 5.9 Hz, 2H), 3.65 (s, 2H), 1.48 (d, J = 6.7 Hz, 6H), 1.09 (s, 9H). 13 13C NMR (150 MHz, DMSO) δ 170.96 (s), 149.44 (s), 147.24 (s), 140.26 (s), 137.12 (s), 135.64 (s), 133.72 (s), 132.87 (s), 132.50 (s), 131.99 (s), 129.27 (s), 127.39 (s), 125.27 (s), 122.20 (s), 121.01 (s), 118.47 (s), 110.88 (s), 109.96 (s), 42.42 (s), 34.41 (s), 33.25 (s), 31.45 (s), 23.04 (s). ESI-HRMS: calcd for C 33 H 35 N 3 O, [M+H] + , 490.2780, found 490.2853.

[0078] Example 13: N-(4-Ethoxybenzyl)-2-(1-isopropyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetamide (Z2-7)

[0079] The compound of Example 13 was prepared in the same manner as in Example 7, except that 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(4-ethoxybenzyl)acetamide was used instead of 2-(5-bromo-1-isopropyl-1H-indol-3-yl)-N-(4-cyanobenzyl)acetamide in the first step, to give a white solid powder with a yield of 31.2%.

[0080] 11H NMR (600 MHz, DMSO) δ 8.97–8.78 (m, 1H), 8.47 (t, J = 5.4 Hz, 1H), 8.39 (d, J = 8.3 Hz, 1H), 8.20 (s, 1H), 8.08 (s, 2H), 8.04 (s, 1H), 7.61 (s, 2H), 7.56–7.53 (m, 1H), 7.40 (s, 1H), 7.13 (d, J = 8.1 Hz, 2H), 6.75–6.56 (m, 2H), 4.82–4.71 (m, 1H), 4.21 (d, J = 5.8 Hz, 2H), 3.76 (q, J = 6.9 Hz, 2H), 3.65 (s, 2H), 1.48 (s, 3H), 1.46 (s, 3H), 1.21 (t, J = 6.9 Hz, 3H). 13 13C NMR (150 MHz, DMSO) δ 170.89 (s), 157.77 (s), 150.56 (s), 147.23 (s), 140.18 (s), 136.40 (s), 135.71–135.57 (m), 131.89 (s), 130.49 (s), 129.73 (s), 129.59 (s), 128.95 (s), 128.73 (d, J = 17.9 Hz), 124.93 (s), 124.67 (s), 122.19 (s), 121.01 (s), 118.42 (s), 114.44 (s), 42.12 (s), 33.26 (s), 22.83 (s). ESI-HRMS: calcd for C 31 1 31 1 3 1 2 , [M+Na] + , 500.2416, found 500.2327.

[0081] Example 14: 2-(1-Isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z3-1)

[0082] Dissolve 5-bromoindole-3-acetic acid (1a, 10.00 g, 39.36 mmol) in 200 mL of anhydrous methanol. Under ice bath conditions, slowly add thionyl chloride (3.2 mL, 43.3 mmol). After the addition is complete, remove the ice bath and react at room temperature for 1 h. After monitoring the reaction to completion by TLC, evaporate the solvent, adjust to about pH 8 with aqueous sodium bicarbonate solution, extract with ethyl acetate (100 mL × 3), combine the organic layers and concentrate to obtain 10.09 g of a brown powdery solid with a yield of 96.7%. Dissolve the intermediate (10.09 g, 37.63 mmol) in 200 mL of toluene, add 6-quinolineboronic acid (7.81 g, 45.16 mmol), add K 3 PO 4 (23.96 g, 112.89 mmol), add 5 mL of water, stir and react at room temperature for 30 min, then add Pd(PPh 3 ) 4(6.96 g, 6.02 mmol). Under nitrogen protection, the reaction was refluxed at 110 °C for 6 h. After monitoring the reaction of the raw materials by TLC and the reaction was completed, the insoluble impurities were removed by filtration, the solvent was concentrated, ethyl acetate (100 mL) was added, and it was washed with saturated brine (100 mL × 2) and then concentrated. Column chromatography (PE:EA = 10:1) gave a yellow oily liquid. Anhydrous ether (20 mL) was added for slurrying, a large amount of solid precipitated, and after suction filtration, it was dried to obtain 3.37 g of a yellow powdery solid with a yield of 28.3%. The intermediate (3.37 g, 10.65 mmol) was dissolved in 100 mL of a methanol solution of NaOH (2 mol / L), stirred and reacted for 2 h, and then monitored by TLC. After the reaction was complete, the reaction solution was concentrated, 200 mL of water was added for dissolution, and the pH was adjusted to 6 - 7 with 1 M hydrochloric acid. After a large amount of solid precipitated, suction filtration was carried out to obtain 3.03 g of a yellow granular solid with a yield of 94.3%. The intermediate (0.25 g, 0.83 mmol) was dissolved in 10 mL of anhydrous DMF, and then NaH (content 60%, 0.10 g, 2.49 mmol) was slowly added portionwise to the solution under an ice bath. After addition, the ice bath was removed, and the reaction was stirred at room temperature for 0.5 h. Then isopropyl bromide (1f, 0.13 g, 0.91 mmol) was slowly added dropwise to the reaction solution, and the reaction was continued to be stirred at room temperature for 1 h and then monitored by TLC. After the reaction was complete, 100 mL of water was added to the reaction solution, and the pH was adjusted to 4 - 5 with 1 M hydrochloric acid. It was extracted with ethyl acetate (30 mL × 3), the organic layers were combined, washed with saturated brine (20 mL × 2) and then concentrated. Column chromatography (DCM:MeOH = 20:1) gave 0.23 g of a brown powdery solid with a yield of 78.70%. The intermediate 1 g (0.20 g, 0.56 mmol) obtained in the previous step was dissolved in 20 mL of anhydrous DMF. HATU (0.26 g, 0.67 mmol) and DIEA (0.22 g, 1.68 mmol) were slowly added under an ice bath. After addition, the ice bath was removed, and the reaction was carried out at room temperature for 0.5 h. After monitoring the reaction of the raw materials by TLC and the reaction was completed, 2-pyridinebenzylamine (2c, 0.07 g, 0.62 mmol) was added, and the reaction was carried out at room temperature for 1 h and then monitored by TLC. After the monitored reaction was completed, 200 mL of water was added to the reaction solution, and it was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine (25 mL × 2) and then concentrated. Column chromatography (PE:EA = 2:1) gave 0.20 g of a yellow powdery solid with a yield of 78.93%.

[0083] 11H NMR (600 MHz, DMSO) δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.58 (t, J = 5.9 Hz, 1H), 8.44–8.37 (m, 2H), 8.23 (d, J = 1.9 Hz, 1H), 8.12 (dd, J = 8.8, 2.0 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 1.2 Hz, 1H), 7.61–7.58 (m, 2H), 7.56 (dd, J = 5.9, 1.8 Hz, 1H), 7.56–7.53 (m, 1H), 7.31 (s, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.17 (dd, J = 7.1, 5.1 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 4.00 (d, J = 7.3 Hz, 2H), 3.71 (s, 2H), 2.14 (dt, J = 13.6, 6.8 Hz, 1H), 0.89 (s, 3H), 0.88 (s, 3H). 13 13C NMR (150 MHz, DMSO) δ 171.28 (s), 159.13 (s), 150.45 (s), 149.22 (s), 147.19 (s), 140.14 (s), 136.96 (s), 136.53 (d, J = 12.6 Hz), 130.42 (s), 129.66 (d, J = 15.9 Hz), 129.15 (s), 128.79 (s), 128.63 (s), 124.99 (s), 122.47 (s), 122.21 (s), 121.40 (s), 121.10 (s), 118.34 (s), 111.07 (s), 109.36 (s), 53.30 (s), 29.30 (s), 20.41 (s). ESI-HRMS: calcd for C 29 H 28 N 4 O, [M + H] + , 449.2263, found 449.2355.

[0084] Example 15: 2-(1-(Cyclobutylmethyl)-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z3-2)

[0085] The compound of Example 15 was prepared in the same manner as in Example 14, except that 2-(1-(cyclobutylmethyl)-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid was used instead of 2-(1-isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid in the fourth step, to give a white solid powder with a yield of 31.2%.

[0086] 1 1H NMR (600 MHz, DMSO) δ 8.87 (dd, J = 4.2, 1.7 Hz, 1H), 8.58 (t, J = 5.9 Hz, 1H), 8.44–8.39 (m, 2H), 8.22 (d, J = 1.9 Hz, 1H), 8.12 (dd, J = 8.8, 2.0 Hz, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.05 (s, 1H), 7.62–7.59 (m, 2H), 7.57 (dd, J = 7.7, 5.9 Hz, 1H), 7.56–7.54 (m, 1H), 7.32 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.17 (dd, J = 6.8, 5.0 Hz, 1H), 4.38 (d, J = 5.9 Hz, 2H), 4.20 (d, J = 7.3 Hz, 2H), 3.70 (s, 2H), 2.81–2.75 (m, 1H), 1.97–1.78 (m, 6H). 13 13C NMR (150 MHz, DMSO) δ 171.27 (s), 159.15 (s), 150.46 (s), 149.24 (s), 147.20 (s), 140.17 (s), 136.96 (s), 136.46 (d, J = 6.2 Hz), 130.43 (s), 129.66 (d, J = 19.4 Hz), 128.91–128.56 (m), 124.98 (s), 122.47 (s), 122.22 (s), 121.44 (s), 121.10 (s), 118.31 (s), 110.91 (s), 109.43 (s), 50.96 (s), 44.77 (s), 36.15 (s), 32.94 (s), 26.05 (s), 18.19 (s). ESI-HRMS: calcd for C 30 H 28 N 4 O, [M+Na] + , 483.2263, found 483.2201.

[0087] Example 16: 2-(1-(Cyclopentylmethyl)-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z3-3)

[0088] The preparation method of the compound of Example 16 is the same as that of Example 14, except that in the fourth step, 2-(1-(cyclopentylmethyl)-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid is used instead of 2-(1-isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid, to obtain a white solid powder with a yield of 24.4%.

[0089] 1 H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.58(t,J=5.9Hz,1H),8.41(ddd,J=9.6,6.7,1.0Hz,2H),8.23(d,J=1.9Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.09(d,J=8.8Hz,1H),8.06(s,1H),7.60(dd,J=6.7,5.0Hz,2H),7.59–7.56(m,1H),7.55(dd,J=7.1,3.0Hz,1H),7.35(s,1H),7.23(d,J=7.8Hz,1H),7.17(dd,J=7.0,5.2Hz,1H),4.38(d,J=5.9Hz,2H),4.10(d,J=7.5Hz,2H),3.71(s,2H),2.40(dd,J=15.0,7.5Hz,1H),1.71–1.39(m,8H). 13 C NMR(150MHz,DMSO)δ171.29(s),159.13(s),150.38–150.25(m),149.20(s),147.16(s),140.20(s),136.97(s),136.47(d,J=15.8Hz),130.42(s),129.65(d,J=10.3Hz),128.83(d,J=10.3Hz),128.66(s),124.98(s),122.47(s),122.21(s),121.43(s),121.09(s),118.34(s),110.94(s),109.39(s),50.54(s),44.76(s),41.05(s),32.95(s),30.37(s),24.93(s).ESI-HRMS:calcd for C 31 H 30 N 4 O,[M+Na] + ,497.2420,found449.2359.

[0090] Example 17: 2-(1-(Cyclopropylmethyl)-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z3-4)

[0091] The preparation method of the compound of Example 17 is the same as that of Example 14, except that in the fourth step, 2-(1-(cyclopropylmethyl)-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid is used instead of 2-(1-isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid, and a white solid powder is obtained with a yield of 24.4%.

[0092] 1 H NMR (600 MHz, DMSO) δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.62 (t, J = 5.9 Hz, 1H), 8.42 (ddd, J = 9.6, 6.7, 1.1 Hz, 2H), 8.23 (d, J = 2.0 Hz, 1H), 8.12 (dd, J = 8.8, 2.1 Hz, 1H), 8.09–8.07 (m, 2H), 7.63 (d, J = 1.0 Hz, 2H), 7.58 (td, J = 7.7, 1.8 Hz, 1H), 7.55 (dd, J = 8.2, 4.2 Hz, 1H), 7.40 (s, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.17 (dd, J = 7.0, 5.2 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 4.06 (d, J = 7.0 Hz, 2H), 3.71 (s, 2H), 1.29–1.26 (m, 1H), 0.55–0.52 (m, 2H), 0.43–0.40 (m, 2H). 13 C NMR (150 MHz, DMSO) δ 171.29 (s), 150.45 (s), 149.24 (s), 147.19 (s), 140.17 (s), 136.98 (s), 136.48 (s), 136.31 (s), 130.45 (s), 129.65 (d, J = 18.6 Hz), 128.76 (d, J = 11.4 Hz), 128.46 (s), 124.97 (s), 122.47 (s), 122.21 (s), 121.45 (s), 121.11 (s), 118.31 (s), 110.95 (s), 109.51 (s), 50.11 (s), 44.79 (s), 32.97 (s), 12.12 (s), 4.22 (s). ESI-HRMS: calcd for C 29 H 26 N 4 O, [M+Na] +,469.2107,found 469.2042.

[0093] Example 18: 2-(1-Ethyl-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z3-5)

[0094] The preparation method of the compound of Example 18 is the same as that of Example 14, except that in the fourth step, 2-(1-ethyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid is used instead of 2-(1-isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid, and a white solid powder is obtained with a yield of 25.5%.

[0095] 1 H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.60(t,J=5.9Hz,1H),8.44–8.39(m,2H),8.23(d,J=1.9Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.09(d,J=8.8Hz,1H),8.07(d,J=1.5Hz,1H),7.63(dd,J=8.5,1.7Hz,1H),7.60–7.57(m,2H),7.55(dd,J=8.2,4.2Hz,1H),7.36(s,1H),7.24(d,J=7.8Hz,1H),7.17(dd,J=7.1,5.2Hz,1H),4.38(d,J=6.0Hz,2H),4.23(q,J=7.2Hz,2H),3.70(s,2H),1.39(t,J=7.2Hz,3H).13C NMR(150MHz,DMSO)δ171.29(s),159.16(s),150.44(s),149.21(s),147.16(s),140.19(s),137.01(s),136.53(s),135.90(s),130.46(s),129.65(d,J=11.9Hz),128.80(s),128.04(s),124.98(s),122.48(s),122.22(s),121.47(s),121.11(s),118.40(s),110.74(s),109.56(s),44.78(s),40.74(s),32.97(s),16.03(s).ESI-HRMS:calcd for C 27 H 24 N 4 O,[M+Na]+,443.1950,found 443.1881.

[0096] Example 19: 2-(1-Propyl-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z3-6)

[0097] The compound of Example 19 was prepared in the same manner as in Example 14, except that in the fourth step, 2-(1-propyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid was used instead of 2-(1-isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid, to obtain a white solid powder with a yield of 28.6%.

[0098] 1 H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.58(t,J=5.9Hz,1H),8.41(ddd,J=9.6,6.7,1.1Hz,2H),8.23(d,J=2.0Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.08(d,J=8.8Hz,1H),8.07(d,J=1.3Hz,1H),7.61(dt,J=15.1,3.9Hz,2H),7.57(dd,J=7.6,5.8Hz,1H),7.56–7.54(m,1H),7.34(s,1H),7.23(d,J=7.8Hz,1H),7.17(dd,J=7.0,5.3Hz,1H),4.38(d,J=6.0Hz,2H),4.15(t,J=7.0Hz,2H),3.70(s,2H),1.80(dd,J=14.3,7.2Hz,2H),0.88(t,J=7.4Hz,3H).13CNMR(150MHz,DMSO)δ171.28(s),159.15(s),150.46(s),149.26(s),147.20(s),140.18(s),136.96(s),136.48(s),136.29(s),130.43(s),129.86(s),129.66(d,J=18.5Hz),128.75(d,J=11.7Hz),124.98(s),122.47(s),122.22(s),121.43(s),121.10(s),118.36(s),110.87(s),109.37(s),47.49–47.35(m),23.66(s),11.66(s).ESI-HRMS:calcd for C 28 H 26 N 4O, [M+Na]+, 457.2107, found 457.2039.

[0099] Example 20: 2-(1-Butyl-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z3-7)

[0100] The preparation method of the compound of Example 20 is the same as that of Example 14, except that in the fourth step, 2-(1-butyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid is used instead of 2-(1-isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid, and a white solid powder is obtained with a yield of 75.28%.

[0101] 1 H NMR(600MHz, DMSO) δ8.88(dd, J=4.2, 1.7Hz, 1H), 8.59(t, J=5.9Hz, 1H), 8.44–8.39(m, 2H), 8.23(d, J=1.9Hz, 1H), 8.13–8.11(m, 1H), 8.08(d, J=8.8Hz, 1H), 8.06(d, J=1.4Hz, 1H), 7.62(dd, J=8.5, 1.7Hz, 1H), 7.59(d, J=3.2Hz, 1H), 7.58–7.56(m, 1H), 7.56–7.54(m, 1H), 7.33(s, 1H), 7.23(d, J=7.8Hz, 1H), 7.17(dd, J=7.4, 4.9Hz, 1H), 4.38(d, J=5.9Hz, 2H), 4.19(t, J=7.0Hz, 2H), 3.70(s, 2H), 1.78–1.73(m, 2H), 1.31–1.27(m, 2H), 0.91(t, J=7.4Hz, 3H). 13C NMR(150MHz, DMSO) δ171.28(s), 159.20(s), 150.45(s), 149.23(s), 147.30(s), 140.18(s), 136.97(s), 136.49(s), 136.23(s), 130.44(s), 129.66(d, J=18.1Hz), 128.91–128.55(m), 124.98(s), 122.47(s), 122.22(s), 121.44(s), 121.11(s), 118.37(s), 110.84(s), 109.45(s), 45.65(s), 44.77(s), 32.95(s), 32.58(s), 20.10(s), 14.09(s). ESI-HRMS: calcd for C 29 H28 N 4 O, [M+H]+, 449.2263, found 449.2336.

[0102] Example 21: 2-(1-(But-3-en-1-yl)-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z3-8)

[0103] The preparation method of the compound of Example 21 is the same as that of Example 2-(1-(but-3-en-1-yl)-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid is used instead of 2-(1-isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid, and the yield is 77.98%.

[0104] 11H NMR (600 MHz, DMSO) δ 8.88 (dd, J = 4.2, 1.7 Hz, 1H), 8.57 (t, J = 5.9 Hz, 1H), 8.42 (dd, J = 13.3, 6.5 Hz, 2H), 8.23 (d, J = 1.9 Hz, 1H), 8.13–8.11 (m, 1H), 8.08 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 1.1 Hz, 1H), 7.63 (dd, J = 8.6, 1.6 Hz, 1H), 7.61–7.59 (m, 1H), 7.58–7.56 (m, 1H), 7.56–7.54 (m, 1H), 7.34 (s, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.17 (dd, J = 7.4, 4.9 Hz, 1H), 5.83 (ddd, J = 17.1, 6.8, 3.5 Hz, 1H), 5.08 (dd, J = 17.2, 1.7 Hz, 1H), 5.01 (dd, J = 10.3, 1.8 Hz, 1H), 4.38 (d, J = 6.0 Hz, 2H), 4.26 (t, J = 7.1 Hz, 2H), 3.70 (s, 2H), 2.57–2.53 (m, 2H). 13C NMR (150 MHz, DMSO) δ 171.25 (s), 159.14 (s), 150.46 (s), 149.23 (s), 147.20 (s), 136.98 (s), 136.50 (s), 136.20 (s), 135.74 (s), 130.50 (s), 129.66 (d, J = 18.1 Hz), 128.77 (d, J = 6.8 Hz), 128.60 (s), 125.00 (s), 122.48 (s), 122.22 (s), 121.45 (s), 121.15 (s), 118.38 (s), 117.65 (s), 110.89 (s), 109.53 (s), 45.42 (s), 44.78 (s), 34.79 (s), 32.95 (s). ESI-HRMS: calcd for C 29 H 26 N 4 O, [M+H]+, 447.2107, found 447.2179.

[0105] Example 22: 2-(1-(2-Methoxyethyl)-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z3-9)

[0106] The preparation method of the compound of Example 22 is the same as that of Example 14, except that in the fourth step, 2-(1-(2-methoxyethyl)-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid is used instead of 2-(1-isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid. A white solid powder is obtained with a yield of 71.23%.

[0107] 1 H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.62(t,J=5.8Hz,1H),8.44–8.39(m,2H),8.23(d,J=1.9Hz,1H),8.12(dd,J=8.8,2.0Hz,1H),8.09(d,J=8.8Hz,1H),8.07(d,J=0.9Hz,1H),7.62(t,J=4.3Hz,1H),7.60(d,J=4.9Hz,1H),7.58(dd,J=7.7,1.8Hz,1H),7.56–7.54(m,1H),7.33(s,1H),7.25(d,J=7.8Hz,1H),7.17(dd,J=6.9,5.2Hz,1H),4.38(d,J=6.0Hz,2H),4.35(t,J=5.3Hz,2H),3.70(s,2H),3.68(t,J=5.3Hz,2H),3.17(s,3H).13C NMR(150MHz,DMSO)δ171.25(s),150.45(s),149.23(s),147.18(s),140.17(s),137.00(s),136.50(d,J=5.4Hz),130.52(s),129.66(d,J=14.4Hz),129.00(s),128.76(d,J=10.2Hz),124.99(s),122.48(s),122.22(s),121.47(s),121.12(s),118.30(s),110.99(s),109.58(s),71.59(s),49.07(s),44.79(s),32.92(s).ESI-HRMS:calcd for C 28 H 26 N 4 O 2 ,[M+H]+,451.2056,found 451.2129.

[0108] Example 23: 2-(1-(2-Methoxyethyl)-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z3-10)

[0109] The preparation method of the compound of Example 23 is the same as that of Example 14, except that in the fourth step, 2-(1-(sec-butyl)-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid is used instead of 2-(1-isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid. A white solid powder was obtained with a yield of 73.26%.

[0110] 1 H NMR(600MHz,DMSO)δ8.88(dd,J=4.2,1.7Hz,1H),8.59(t,J=5.9Hz,1H),8.42(ddd,J=9.5,6.6,0.9Hz,2H),8.23(d,J=1.9Hz,1H),8.13–8.12(m,1H),8.09(d,J=8.8Hz,1H),8.07(d,J=1.1Hz,1H),7.63(d,J=8.6Hz,1H),7.61(dd,J=8.6,1.6Hz,1H),7.58–7.56(m,1H),7.55(dd,J=7.3,3.2Hz,1H),7.42(s,1H),7.24(d,J=7.8Hz,1H),7.17(dd,J=7.1,5.2Hz,1H),4.56–4.51(m,1H),4.39(d,J=5.9Hz,2H),3.72(s,2H),1.88–1.81(m,2H),1.47(d,J=6.7Hz,3H),0.76(t,J=7.3Hz,3H).13C NMR(150MHz,DMSO)δ159.08(s),150.39(s),149.14(s),147.11(s),140.20–140.07(m),137.01(s),136.57(s),136.35(s),130.41(s),129.64(s),128.81(s),128.51(s),124.98(d,J=9.0Hz),122.53(s),122.22(s),121.48(s),121.02(s),118.35(s),110.93(s),110.01(s),44.59(s),21.20(s),11.23(s).ESI-HRMS:calcd for C 29 H 28 N 4 O,[M+H]+,449.2263,found 449.2336.

[0111] Example 24: 2-(1-(Pentan-3-yl)-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z3-11)

[0112] The preparation method of the compound of Example 24 is the same as that of Example 14, except that 2-(1-(pentan-3-yl)-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid is used instead of 2-(1-isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid in the fourth step, and a white solid powder is obtained with a yield of 71.42%.

[0113] 1 H NMR (600 MHz, DMSO) δ 8.88 (dd, J = 4.1, 1.7 Hz, 1H), 8.55 (t, J = 5.9 Hz, 1H), 8.41 (t, J = 7.2 Hz, 2H), 8.22 (d, J = 1.9 Hz, 1H), 8.12 (dd, J = 8.8, 2.0 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 8.6, 1.7 Hz, 1H), 7.58–7.56 (m, 1H), 7.55 (dd, J = 4.8, 3.3 Hz, 1H), 7.38 (s, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.17 (dd, J = 7.4, 4.9 Hz, 1H), 4.39 (d, J = 5.9 Hz, 2H), 4.31–4.26 (m, 1H), 3.72 (s, 2H), 1.90–1.83 (m, 4H), 0.71 (t, J = 7.3 Hz, 6H). 13C NMR (151 MHz, DMSO) δ 171.28 (s), 159.09 (s), 150.41 (s), 149.20 (s), 147.14 (s), 140.24 (s), 137.34 (s), 136.97 (s), 136.53 (s), 130.38 (s), 129.65 (d, J = 5.9 Hz), 128.80 (s), 128.33 (s), 125.02 (d, J = 15.8 Hz), 122.49 (s), 122.21 (s), 121.40 (s), 121.07 (s), 118.33 (s), 110.95 (s), 110.33–110.20 (m), 59.20 (s), 33.29 (s), 28.52 (s), 11.16 (s). ESI-HRMS: calcd for C 30 H 30 N 4O, [M+H]+, 463.2420, found 464.2492.

[0114] Example 25: 2-(1-(2-Ethoxyethyl)-5-(quinolin-6-yl)-1H-indol-3-yl)-N-(pyridin-2-ylmethyl)acetamide (Z-25)

[0115] The preparation method of the compound of Example 25 is the same as that of Example 14, except that in the fourth step, 2-(1-(2-ethoxyethyl)-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid is used instead of 2-(1-isobutyl-5-(quinolin-6-yl)-1H-indol-3-yl)acetic acid, and a white solid powder is obtained with a yield of 68.33%.

[0116] 1 H NMR(600MHz, DMSO) δ8.80(dd, J = 4.1, 1.5Hz, 1H), 8.54(t, J = 5.9Hz, 1H), 8.34(dd, J = 19.6, 6.5Hz, 2H), 8.16(d, J = 1.6Hz, 1H), 8.05(dd, J = 8.8, 1.9Hz, 1H), 8.02(d, J = 8.9Hz, 1H), 8.00(s, 1H), 7.57–7.52(m, 2H), 7.52–7.49(m, 1H), 7.47(dd, J = 8.2, 4.2Hz, 1H), 7.27(s, 1H), 7.17(d, J = 7.8Hz, 1H), 7.09(dd, J = 7.3, 5.0Hz, 1H), 4.32(d, J = 5.9Hz, 2H), 4.26(t, J = 5.4Hz, 2H), 3.66–3.61(m, 4H), 3.35(q, J = 7.0Hz, 2H), 0.99(t, J = 7.0Hz, 3H). 13C NMR(150MHz, DMSO) δ171.27(s), 159.14(s), 150.44(s), 149.22(s), 147.19(s), 140.16(s), 136.98(s), 136.55(d, J = 13.4Hz), 130.51(s), 129.65(d, J = 18.1Hz), 129.01(s), 128.77(d, J = 9.0Hz), 124.98(s), 122.47(s), 122.21(s), 121.46(s), 121.09(s), 118.29(s), 111.01(s), 109.59(s), 69.53(s), 65.83(s), 46.10(s), 44.70(s), 32.94(s). ESI-HRMS: calcd for C 29 H28 N 4 O 2 , [M+H]+, 465.2212, found 465.2285.

[0117] Example 26: Pharmacological Study of the Product of the Invention

[0118] Pharmacological tests have demonstrated that the compounds involved in the present invention have anti-pancreatic cancer metastasis activity.

[0119] (1) MTT Cytotoxicity Experiment

[0120] Using the MTT cytotoxicity experiment, the cytotoxic effects of the test compounds at different concentrations on BxPC-3 cells will be examined.

[0121] Take BxPC-3 cells in the logarithmic growth phase and inoculate them into 96-well plates at a cell density of 6×10 4 cells / mL. After the cells adhere to the wall, add 100 μL of drug-containing culture medium with different concentrations prepared in serum-free culture medium to the drug administration wells, and add an equal volume of serum-free culture medium containing DMSO (0.1%) to the control group. After continuous culture for 48 h, add MTT (15 μL) working solution to each well and incubate for 4 h. Subsequently, discard all the liquid, add 150 μL of DMSO to each well and shake for 10 min to fully dissolve the crystals. Then, measure the absorbance (OD) value at a wavelength of 492 nm using a multi-functional microplate reader. Calculate the cell survival rate according to the formula.

[0122] The experimental results are shown in Table 1, Table 2, and Figure 1 , Figure 2 as shown.

[0123] Table 1. Survival Rate Test of Compounds Z1-1 to Z1-6 on BxPC-3 Cells

[0124]

[0125]

[0126] Table 2. Survival Rate Test of Compounds Z2-1 to Z2-7 on BxPC-3 Cells

[0127]

[0128] (2) Scratch Experiment to Test the Activity of Compounds against Pancreatic Cancer Metastasis

[0129] Take BxPC-3 cells in the logarithmic growth phase to prepare a cell suspension, count them, and dilute the cell concentration to 3×10 5Add 2 mL to each well of a 6-well plate after mixing. Scratching can be performed only after the monolayer cells cover the bottom of the wells. Use a 10-μL pipette tip to make scratches, with 3 scratches formed in each well. After scratching, discard the original culture medium, wash the floating cells after scratching with sterile PBS, and repeat 3 times. Finally, add 2 mL of the drug-containing culture medium prepared with culture medium without FBS to the drug administration wells, and add an equal volume of culture medium containing 0% FBS to the control group, and culture in an incubator for 48 h. Select two time points, 0 h and 48 h, for sampling and photographing. Open the cell scratch photos with ImageJ software, randomly draw 6 straight lines at each scratch, measure the distances between the straight lines, calculate the average value, and calculate the relative migration rate using the calculation formula.

[0130] The experimental results are as Figure 3 ( Figure 3 A- Figure 3 B), Figure 4 as shown.

[0131] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalent technologies, the present invention is also intended to include these changes and modifications.

Claims

1. An indole compound represented by General Formula I having anti-pancreatic cancer metastasis activity or a pharmaceutically acceptable salt thereof, Characterized in that: ； wherein R 1 is selected from a quinoline ring or an isoquinoline ring; R 2 is selected from C 1-6 alkyl, C 3-8 cycloalkyl or C 2-6 alkenyl; R3 is selected from benzyl, a pyridine ring or a thiophene ring substituted with one or more substituents of C 1-6 alkyl, C 1-6 alkoxy or cyano.

2. A compound having anti-pancreatic cancer metastasis activity or a pharmaceutically acceptable salt thereof, Characterized in that: The compound is selected from: ； ； ； 。 3. A pharmaceutical composition, Characterized in that: The pharmaceutical composition comprises the compound or a pharmaceutically acceptable salt thereof according to Claim 1 or Claim 2 and a pharmaceutically acceptable carrier.

4. A pharmaceutical preparation, Characterized in that: The pharmaceutical preparation comprises the pharmaceutical composition according to Claim 3, and the dosage form of the pharmaceutical preparation is selected from one or more of the following: tablets, capsules, injections, suppositories, patches, inhalable powder preparations, suspensions, emulsions or ointments.

5. Use of the compound or a pharmaceutically acceptable salt thereof according to Claim 1 or Claim 2, or the pharmaceutical composition according to Claim 3, or the pharmaceutical preparation according to Claim 4 in the preparation of an SIRT2 inhibitor.

6. Use of the compound or a pharmaceutically acceptable salt thereof according to Claim 1 or Claim 2, or the pharmaceutical composition according to Claim 3, or the pharmaceutical preparation according to Claim 4 in the preparation of an anti-tumor drug.

7. According to the use described in Claim 6, Characterized in that: The anti-tumor drug has anti-pancreatic cancer metastasis activity.

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